Over 50% of children with multiple malformations seen in medical genetics clinics for a suspected genetic syndrome never receive a diagnosis, which leaves unanswered questions about prognosis and medical/reproductive planning. While individual multiple malformation syndromes (MMS) are rare diseases (many <1 in 200,000 births), in combination, these conditions are costly and medically severe. There have been some recent successes in developing orphan treatments for some of these rare syndromes, but this only represents the ?tip of the iceberg,? and it is thought that there are many more recognized and unrecognized MMS that will be amenable to new therapies. The next steps toward identifying therapeutic targets and biomarkers of outcomes for these rare diseases are to 1) identify these MMS, 2) characterize their clinical profile, and 3) uncover the underlying genetic causes. To accomplish these goals, we will first identify ?new? MMS (i.e., not described in the literature) using international data from two large networks that represent most of the major birth defects registries worldwide. By leveraging these population-based data, we will address the limitations of previous approaches for identifying new MMS (i.e., clinical case reports based on a small number of cases identified in a single clinic). Second, we will verify the occurrence of ?unconfirmed? MMS (i.e., unconfirmed case reports of only a few cases) using our international network of birth defects registries to address the possibility that that the malformations patterns reported in these previous case reports occurred due to chance alone. We will use a network of medical genetics clinics we have assembled to recruit clinical patients with the new MMS and the unconfirmed MMS that we validate. We will conduct systematic phenotyping of these cases to better delineate the clinical profiles of these syndromes. We will also collect DNA samples from these patients and their families and conduct exome sequencing, which may identify pathways that could lead to therapeutic targets for these rare but clinically significant conditions.